1. Field of the Invention
The present invention relates to biodegradable homopolymer and block copolymer compositions, in particular those containing both phosphate and terephthalate ester linkages in the polymer backbone, which degrade in vivo into non-toxic residues. The polymers of the invention are particularly useful as implantable medical devices and drug delivery systems.
2. Description of the Prior Art
Biocompatible polymeric materials have been used extensively in therapeutic drug delivery and medical implant device applications. Sometimes, it is also desirable for such polymers to be, not only biocompatible, but also biodegradable to obviate the need for removing the polymer once its therapeutic value has been exhausted.
Conventional methods of drug delivery, such as frequent periodic dosing, are not ideal in many cases. For example, with highly toxic drugs, frequent conventional dosing can result in high initial drug levels at the time of dosing, often at near-toxic levels, followed by low drug levels between doses that can be below the level of their therapeutic value. However, with controlled drug delivery, drug levels can be more easily maintained at therapeutic, but non-toxic, levels by controlled release in a predictable manner over a longer term.
If a biodegradable medical device is intended for use as a drug delivery or other controlled-release system, using a polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., xe2x80x9cChemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agentsxe2x80x9d, J. Macro. Science, Rev. Macro. Chem. Phys., C23:1, 61-126 (1983). As a result, less total drug is required, and toxic side effects can be minimized. Polymers have been used as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., xe2x80x9cPolymeric Controlled Drug Deliveryxe2x80x9d, Advanced Drug Delivery Reviews, 1:199-233 (1987); Langer, xe2x80x9cNew Methods of Drug Deliveryxe2x80x9d, Science, 249:1527-33 (1990); and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity.
For a non-biodegradable matrix, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and diffusion of the therapeutic agent out through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is longer for a non-biodegradable matrix than for a biodegradable matrix, for which passage through the channels of the matrix, while it may occur, is no longer required. Since many pharmaceuticals have short half-lives, therapeutic agents can decompose or become inactivated within the non-biodegradable matrix before they are released. This issue is particularly significant for many bio-macromolecules and smaller polypeptides, since these molecules are generally hydrolytically unstable and have low permeability through a polymer matrix. In fact, in a non-biodegradable matrix, many bio-macromolecules aggregate and precipitate, blocking the channels necessary for diffusion out of the carrier matrix.
These problems are alleviated by using a biodegradable matrix that, in addition to some diffusion release, also allows controlled release of the therapeutic agent by degradation of the polymer matrix. Examples of classes of synthetic polymers that have been studied as possible biodegradable materials include polyesters (Pitt et al., xe2x80x9cBiodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Application to contraceptives and Narcotic Antagonistsxe2x80x9d, Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al., xe2x80x9cTrends in the Development of Bioresorbable Polymers for Medical Applicationsxe2x80x9d, J. of Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., xe2x80x9cBiodegradable Lysine Diisocyanate-based Poly(Glycolide-co-xcex5 Caprolactone)-Urethane Network in Artificial Skinxe2x80x9d, Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al., xe2x80x9cRelease of Norethindrone from Poly(Ortho Esters)xe2x80x9d, Polymer Engineering Sci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al., xe2x80x9cPolyanhydrides for Controlled Release of Bioactive Agentsxe2x80x9d, Biomaterials 7:5, 364-71 (1986). Specific examples of biodegradable materials that are used as medical implant materials are polylactide, polyglycolide, polydioxanone, poly(lactide-co-glycolide), poly(glycolide-co-polydioxanone), polyanhydrides, poly(glycolide-co-trimethylene carbonate), and poly(glycolide-co-caprolactone).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: xe2x80x9cPhosphorus-Containing Polymersxe2x80x9d, (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, is as follows: 
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or Rxe2x80x2 group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the sidechain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with xe2x80x94O-carboxy groups may be coupled to the phosphorus via an ester bond, which is hydrolyzable. The Pxe2x80x94Oxe2x80x94C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
Login et al., in U.S. Pat. Nos. 4,259,222; 4,315,847; and 4,315,969, disclose a poly(phosphate)-polyester polymer having a halogenated terephthalate recurring unit useful in flame retardant materials, but without a phosphorus having a side chain.
Kadiyala et al., Biomedical Applications of Synthetic Biodegradable Polymers, Chapter 3: xe2x80x9cPoly(phosphoesters): Synthesis, Physicochemical Characterization and Biological Responsexe2x80x9d, 33-57 (Jeffrey O. Hollinger ed., 1995) at page 40 discloses the synthesis of bis(2-hydroxyethyl)terephthalate (BHET) and its subsequent reaction with dimethyl phosphite to form the corresponding poly(phosphite): 
A number of other patents disclose flame retardants having a polyester-linked terephthalate recurring unit and may also have a poly(phosphonate) recurring unit having a xe2x80x94Pxe2x80x94Rxe2x80x2 side chain in which an Rxe2x80x2 group has replaced the hydrogen atom of a poly(phosphite), but lacking the intervening oxygen of a poly(phosphate). See, for example, Desitter et al., U.S. Pat. No. 3,927,231 and Reader, U.S. Pat. No. 3,932,566. Starck et al., U.S. Pat. No. 597,473 disclose side chains that can be substituted with many kinds of groups including an alkoxy group, but the document as a whole makes it clear that poly(phosphonates), rather than poly(phosphates), are contemplated. (See column 2, lines 28-40.)
Engelhardt et al., U.S. Pat. No. 5,530,093 discloses a multitude of textile finishing compositions having a wide variety of polycondensate structures with phosphoester recurring units, including some with terephthalate recurring units, but no guidance is provided to indicate that poly(phosphates), rather than the other two classes of phosphoester polymers, should be selected for making biodegradable materials.
Thus, there remains a need for materials such as the terephthalate polyester-poly(phosphate) polymers of the invention, which are particularly well-suited for making biodegradable materials and other biomedical applications.
The biodegradable terephthalate polymers of the invention comprise the recurring monomeric units shown in formula I: 
wherein R is a divalent organic moiety;
Rxe2x80x2 is an aliphatic, aromatic or heterocyclic residue;
x is xe2x89xa71; and
n is 0-5,000,
where the biodegradable polymer is sufficiently pure to be biocompatible and degrades to biocompatible residues upon biodegradation.
In another embodiment, the invention contemplates a process for preparing a biodegradable terephthalate homopolymer comprising the step of polymerizing p moles of a diol compound having formula II: 
wherein R is as defined above, with q moles of a phosphoro-dichloridate of formula III: 
wherein Rxe2x80x2 is defined as above, and p greater than q, to form q moles of a homopolymer of formula IV, shown below: 
wherein R, Rxe2x80x2 and x are as defined above.
The invention also contemplates a process for preparing a biodegradable block copolymer comprising the steps of:
(a) the polymerization step discribed above; and
(b) further reacting the homopolymer of formula IV and excess diol of formula II with (p-q) moles of terephthaloyl chloride having the formula V: 
to form a block copolymer of formula I.
In another embodiment, the invention comprises a biodegradable terephthalate polymer composition comprising:
(a) at least one biologically active substance and
(b) a polymer having the recurring monomeric units shown in formula I.
In yet another embodiment of the invention, an article useful for implantation, injection, or otherwise being placed totally or partially within the body, comprises the biodegradable terephthalate polymer of formula I or the above-described polymer composition.
In yet another embodiment of the invention, a method is provided for the controlled release of a biologically active substance comprising the steps of:
(a) combining the biologically active substance with a biodegradable terephthalate polymer having the recurring monomeric units shown in formula I to form an admixture;
(b) forming the admixture into a shaped, solid article; and
(c) implanting or injecting the solid article in vivo at a preselected site, such that the solid implanted or injected article is in at least partial contact with a biological fluid.